‘Fatty blood’ early warning sign of Alzheimer’s

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Behind the Headlines

Friday July 20 2012

Could blood tests be used to screen for Alzheimer’s?

“High levels of fat in the blood could be an early warning of Alzheimer’s disease,” says the Daily Express. The newspaper reports that people with high levels of a fatty compound called ceramide in their blood are 10 times more likely to develop the disease than people with the lowest levels.

This news is based on a small study that followed 99 initially dementia-free women in their seventies for almost a decade. While the study was well designed and does seem to suggest a link between ceramide levels and risk of Alzheimer’s disease, it has some limitations, in particular its size. Because the study was so small, the results could have occurred by chance.

Overall, the findings of this preliminary study suggest that the role of ceramides in Alzheimer’s disease may be worth further investigation. If it is confirmed that a rise in ceramide levels is associated with the onset of Alzheimer’s disease this will provide a greater insight into the underlying biology of the condition.

But, even if this kind of testing does provide an “early warning” sign of Alzheimer’s disease it is still unclear how it could contribute to the development of methods to slow the progression of the condition.

Where did the story come from?

The study was carried out by researchers from the Mayo Clinic and universities in the US. It was funded by the National Institute on Aging, the National Institute of Neurological Disorders and Stroke, and the Johns Hopkins Older Americans Independence Center. It was published in the peer-reviewed medical journal Neurology.

Both the Daily Express and Daily Mail’s stories include quotes that make it clear that more research is needed.

What kind of research was this?

This was a prospective cohort study that looked at the relationship between the level of two types of fatty molecules in the blood and dementia. This type of study design is the best way to investigate this potential relationship.

The fatty molecules investigated in the study were sphingomyelins and ceramides, which are found in high levels in the membranes that surround cells. The breakdown of sphingomyelins is one way ceramides are formed. Ceramides play various roles in cells, including regulating cell survival. They are also involved in how precursors of amyloid – one of the proteins implicated in Alzheimer’s disease – are formed, processed and moved around the cell. The formation of insoluble amyloid plaques in the brain is one of the hallmarks of Alzheimer’s disease.

The researchers say that few studies have actually looked at the relationship between these fatty molecules and Alzheimer’s disease in humans. They wanted to look at whether their levels in the blood predicted risk of all forms of dementia or just Alzheimer’s disease.

What did the research involve?

The researchers assessed women taking part in the Women’s Health and Aging Study II (WHAS II) in the US, which is an ongoing study that was launched in 1994 to assess the effects of ageing on a number of different health issues, including dementia and Alzheimer’s disease. This study included the most able 70-79 year olds, who did not have dementia or significant problems with physical function at the start of the study.

For the current analysis, the researchers randomly selected 100 women who had provided blood samples at the start of the study. One of these women was found to have dementia at the start of the study and was excluded from analyses. The researchers measured levels of ceramides in these samples.

The women had thorough medical assessments and examinations, including neurological tests, every 1.5 to 3 years, for 9 years. Women whose cognitive performance had decreased significantly since their last examination or dropped below a certain level were identified. The full medical records for these women were assessed by a panel of medical experts, who determined whether the women had mild cognitive impairment or dementia based on standard, accepted criteria.

Alzheimer’s disease is one cause of dementia, and the diagnosis is usually only reliably confirmed on examination of the brain after death. While a patient is alive they are categorised according to how likely it is that they have Alzheimer’s disease based on their signs and symptoms. The researchers also determined whether women with dementia had possible and probable Alzheimer’s disease, again based on standard, accepted criteria.

The researchers looked at whether blood ceramide and sphingomyelin levels at the start of the study predicted which women were more likely to go on to have dementia or Alzheimer’s disease specifically. To do this, the researchers compared risk of dementia and Alzheimer’s disease in those with the lowest third of levels of blood ceramide and sphingomyelin with those with the middle third of levels (moderate levels) and the highest third of levels.

In their analyses, they took into account other differences between the women, including:

age

ethnicity

education

smoking

physical activity

body mass index

medical conditions

symptoms

medication use

levels of other molecules in the blood, such as cholesterol

What were the basic results?

During the study, 27 women developed dementia (27.3%), and 18 were considered to have probable Alzheimer’s disease (18.2%).

There was no relationship between sphingomyelin levels at the start of the study and risk of dementia and Alzheimer’s disease specifically. There was also no relationship between cholesterol levels in the blood and risk of dementia as a whole or of Alzheimer’s disease specifically. In contrast, women with higher levels of ceramide in the blood at the start of the study were more likely to develop any type of dementia and Alzheimer’s disease specifically.

The ceramides can be classified according to the length of the carbon chain that makes them up. Compared with those with the lowest levels of one particular ceramide with a 16 carbon molecule chain, those with moderate levels were 10 times more likely to develop Alzheimer’s disease during the study (hazard ratio [HR] 10.0, 95% confidence interval [CI] 1.2 to 85.1).

There was a trend for increased risk of Alzheimer’s disease in people with the highest levels of this ceramide, but the increase was not large enough to reach statistical significance.

Compared to those with the lowest levels of a ceramide with a 24 carbon molecule chain, those with the highest levels were about five times more likely to develop Alzheimer’s disease during the study (HR 5.1, 95% CI 1.1 to 23.6). Those with the highest levels of a type of ceramide called lactosylceramide were at almost 10 times the risk of Alzheimer’s disease compared with those with the lowest levels (HR 9.8, 95% CI 1.2 to 80.1).

There were similar findings for dementia as a whole, but the effect of ceramide levels was less pronounced.

How did the researchers interpret the results?

The researchers concluded that high levels of particular ceramides in the blood were associated with an increased risk of all-cause dementia independent of other factors such as age and body mass index. They say that ceramides could be potential new targets for the prevention or treatment of Alzheimer’s disease.

Conclusion

This study has found a link between the levels of the fatty molecules ceramides in the blood in older women and risk of developing Alzheimer’s disease. The study’s strength is that it followed women up in a prospective fashion, and performed thorough medical assessments to see if they had developed dementia.

There are some limitations, mainly that the study was small – only assessing 99 women, 18 of whom developed Alzheimer’s. When the women were analysed according to their ceramide levels, the numbers in the groups would be even smaller. Results obtained from small groups of people may not be representative of the population as a whole, and should be confirmed by larger studies. These larger studies should ideally include men as well as women, to see if the results apply to both sexes. Future studies could also measure ceramide levels at more than one point in time, as the levels may change over time. The other main limitation of the study is that it carried out multiple statistical tests, and the more tests carried out the greater the likelihood of finding an association that is just due to chance.

Overall, the findings of this preliminary study suggest that the role of ceramides in Alzheimer’s disease may be worth further investigation. Much more research will be needed to determine whether they could be worth considering as “new targets” for drug development to potentially prevent or treat Alzheimer’s.